In sub-Saharan Africa and southeast Asia, invasive cryptococcal disease is the second most common life- threatening opportunistic infection after tuberculosis and is responsible for up to 20% of deaths. As anti- retroviral and antifungal therapies become more available in resource-limited settings, there has been growing interest in developing new approaches to improve outcomes from invasive cryptococcal infection. Since invasive cryptococcal disease primarily affects HIV-individuals with advanced immunosuppression, one potential strategy to identify early cryptococcal infection in resource-limited settings is to screen asymptomatic individuals with advanced HIV-related immunosuppression for serum cryptococcal antigen (CrAg) as they enter outpatient HIV care and treatment programs. Several observational cohort studies have demonstrated that this approach clearly identifies a population at high risk of cryptococcal meningitis and death and is a feasible screening method for resource-limited settings. However, screening with serum CrAg alone without additional diagnostic studies identifies a heterogeneous clinical population with early cryptococcal infection, many of whom already have sub-clinical meningeal infection or fungemia. Although the mainstay of anti-cryptococcal therapy in resource-limited settings is monotherapy with oral fluconazole, preliminary evidence suggests this is not an effective treatment in a heterogeneous population of individuals with early cryptococcal infection. Thus, there is a critical need for potent therapies that are effective in a heterogeneous population of HIV-infected individuals with advanced immunosuppression and early cryptococcal infection and which can be safely administered in resource-limited settings. Although there are no randomized controlled trials of therapies for early cryptococcal infection, combination therapy with oral high-dose fluconazole and flucytosine has shown promise in small clinical trials for the treatment of cryptococcal meningitis. In this open-label Phase IIb randomized controlled clinical trial based at Family AIDS Care and Education Services (FACES) in Western Kenya, we will determine the safety and estimate the efficacy of combination therapy with oral flucytosine and fluconazole as compared to fluconazole monotherapy for the treatment of early cryptococcal infection in HIV-infected individuals with advanced immunosuppression who have no signs of meningitis or severe, systemic cryptococcal infection. In a sub-sample of trial participants, we will conduct additional diagnostic studies to further characterize the nature of early cryptococcal infection in our setting. Finally, through a new research collaboration which builds on existing relationships, we will conduct a series of activities intended to build research capacity in Kenya at the University of Nairobi and FACES. PUBLIC HEALTH RELEVANCE: Cryptococcal meningitis is a leading cause of death in HIV-infected individuals. In this study we will test a new combination of medicines for the treatment of early cryptococcal infection in individuals with advanced HIV. We will determine if this treatment is at least as safe as standard treatments in preventing death from cryptococcal meningitis.